a. The endoplasmic reticulum (ER) is an important organelle that responds to multiple nutrient-associated signals, such as those induced by fatty acids, glucose, free cholesterol, insulin and amino acids. The unfolded-protein response (UPR) is induced in response to ER stress and activates stress-response pathways (not shown) and inflammatory signalling pathways that can result in altered metabolic and inflammatory responses and consequently in metabolic disease. The inflammatory response can enhance the UPR and further activate mammalian target of rapamycin (mTOR). b. The UPR is mediated by three different pathways that are initiated by three transmembrane proteins that are located in the ER — activating transcription factor 6 (ATF6), pancreatic ER kinase (PERK) and inositol-requiring kinase 1 (IRE1). ER stress is linked to inflammation through the activation of the JUN N-terminal kinase (JNK) and the IκB kinase (IKK)–nuclear factor-κB (NFκB) pathways, and through cyclic-AMP-responsive-element-binding protein H (CREBH) activation by the UPR. These pathways result in the induction of an inflammatory response. Activation of JNK can also serine phosphorylate insulin receptor substrate 1 (IRS1), resulting in altered metabolic responses. Key organelles for cellular metabolism, such as the ER, Golgi, mitochondria and peroxisomes (not shown) are connected through an endomembrane network, which provides functional continuity between organelles that can therefore share functional information in the form of lipids and proteins at specific contact sites. This functional and molecular integration between the organelles can mediate the spread of stress from one organelle to the other, resulting in exacerbation of inflammation and cytotoxicity during chronic metabolic stress conditions such as obesity and dyslipidaemia. AP1, activator protein 1; ATF6f, ATF6 fragment; eIF2α, eukaryotic translation initiation factor 2α; IκB, inhibitor of NFκB; XBP1s, spliced X-box binding protein 1.